The present invention relates to cyclized amide derivatives for treating or preventing neuronal damage associated with neurological diseases. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage.
Neurological diseases are associated with the death of or injury to neuronal cells. Typical treatment of neurological diseases involves drugs capable of inhibiting neuronal cell death. A more recent approach involves the promotion of nerve regeneration by promoting neuronal growth.
Neuronal growth, which is critical for the survival of neurons, is stimulated in vitro by nerve growth factors (NGF). For example, Glial Cell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for the treatment of Parkinson""s disease. Insulin and insulin-like growth factors have been shown to stimulate growth of neurites in rat pheochromocytoma PC12 cells and in cultured sympathetic and sensory neurons [Recio-Pinto et al., J. Neurosci., 6, pp. 1211-1219 (1986)]. Insulin and insulin-like growth factors also stimulate the regeneration of injured motor nerves in vivo and in vitro [Near et al., Proc. Natl. Acad. Sci., pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodarowicz et al., Cell Differ., 19, p. 1 (1986)] and growth [M. A. Walter et al., Lymphokine Cytokine Res., 12, p. 135 (1993)].
There are, however, several disadvantages associated with the use of nerve growth factors for treating neurological diseases. They do not readily cross the blood-brain barrier. They are unstable in plasma and they have poor drug delivery properties.
Recently, small molecules have been shown to stimulate neurite outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neuronal growth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [(C. Dominique Toran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp. 169-78 (1996); and B. S. McEwen et al., Brain Res. Dev. Brain. Res., 87, pp. 91-95 (1995)]. The progress of Alzheimer""s disease is slowed in women who take estrogen. Estrogen is hypothesized to complement NGF and other neurotrophins and thereby help neurons differentiate and survive.
Other target sites for the treatment of neurodegenerative disease are the immunophilin class of proteins. Immunophilins are a family of soluble proteins that mediate the actions of immunosuppressant drugs such as cyclosporin A, FK506 and rapamycin. Of particular interest is the 12 kDa immunophilin, FK-506 binding protein (FKBP12). FKBP12 binds FK-506 and rapamycin, leading to an inhibition of T-cell activation and proliferation. Interestingly, the mechanism of action of FK-506 and rapamycin are different. For a review, see, S. H. Solomon et al., Nature Med., 1, pp. 32-37 (1995). It has been reported that compounds with an affinity for FKBP12 that inhibit that protein""s rotomase activity possess nerve growth stimulatory activity. [Lyons et al., Proc. Natl. Acad. Sci. USA, 91, pp. 3191-3195 (1994)]. Many of these such compounds also have immunosuppressive activity.
FK506 (Tacrolimus) has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al. (1994)]. This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve [B. Gold et al., J. Neurosci., 15, pp. 7509-16 (1995)].
The use of immunosuppressive compounds, however, has drawbacks in that prolonged treatment with these compounds can cause nephrotoxicity [Kopp et al., J. Am. Soc. Nephrol., 1, p. 162 (1991)], neurological deficits [P. C. DeGroen et al., N. Eng. J. Med., 317, p. 861 (1987)] and vascular hypertension [Kahan et al., N. Eng. J. Med., 321, p. 1725 (1989)].
More recently, sub-classes of FKBP binding compounds which inhibit rotomase activity, but which purportedly lack immunosuppressive function have been disclosed for use in stimulating nerve growth [see, U.S. Pat. No. 5,614,547; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner et al., Proc. Natl. Acad. Sci. USA, 94, pp. 2019-23 (1997); and G. S. Hamilton et al., Bioorg. Med. Chem. Lett., 7, pp. 1785-90 (1997)].
Stimulation of neural axons in nerve cells by piperidine derivatives is described in WO 96/41609. Clinical use of the piperidine and pyrrolidine derivatives known so far for stimulating axonal growth has not been promising, as the compounds are unstable in plasma and do not pass the blood-brain barrier in adequate amounts.
Though a wide variety of neurological degenerative diseases may be treated by promoting repair of neuronal damage, there are relatively few agents known to possess these properties. Thus, there remains a need for new compounds and compositions that have the ability to either prevent or treat neuronal damage associated with neuropathological diseases.
The present invention provides compounds having formula (I): 
and pharmaceutically acceptable derivatives thereof, wherein:
A and B are independently E, (C1-C10)-straight or branched alkyl, (C2-C10)-straight or branched alkenyl or alkynyl, or (C5-C7)-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (C5-C7)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the xe2x80x94CH2xe2x80x94 groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90 or xe2x80x94N(R3)xe2x80x94;
or, B is hydrogen;
wherein R3 is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C4)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl, wherein a bridge is formed between the nitrogen atom to which said R3 is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, and wherein said ring is optionally benzofused;
wherein E is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, O or S; and wherein no more than 4 ring atoms are selected from N, O or S;
wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, Oxe2x80x94[(C1-C6)-straight or branched alkyl], Oxe2x80x94[(C3-C6)-straight or branched alkenyl], (CH2)nxe2x80x94N(R4) (R5), (CH2) nxe2x80x94NH (R4)xe2x80x94(CH2)nxe2x80x94Z, (CH2)nxe2x80x94N(R4xe2x80x94(CH2)nxe2x80x94Z) (R5xe2x80x94(CH2)nxe2x80x94Z), (CH2)nxe2x80x94Z, Oxe2x80x94(CH2)nxe2x80x94Z, (CH2)nxe2x80x94Oxe2x80x94Z, Sxe2x80x94(CH2)nxe2x80x94Z, CHxe2x95x90CHxe2x80x94Z, 1,2-methylenedioxy, C(O)OH, C(O)Oxe2x80x94[(C1-C6)-straight or branched alkyl], C(O)Oxe2x80x94(CH2)nxe2x80x94Z or C(O)xe2x80x94N(R4) (R5);
wherein each of R4 and R5 are independently hydrogen, (C1-C6)-straight or branched alkyl, (C3-C5)-straight or branched alkenyl, or wherein R4 and R5, when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, O or S; wherein said alkyl, alkenyl or alkynyl groups in R4 and R5 are optionally substituted with Z.
each n is independently 0 to 4;
each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, O or S; and wherein no more than 4 ring atoms are selected from N, O or S;
wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(O)OH, (C1-C3)-straight or branched alkyl, Oxe2x80x94(C1-C3)-straight or branched alkyl, C(O)Oxe2x80x94[(C1-C3)-straight or branched alkyl], amino, NH [(C1-C3)-straight or branched alkyl], or Nxe2x80x94[(C1-C3)-straight or branched alkyl]2;
J is selected from H, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E;
wherein J is optionally substituted with up to 3 substituents selected from halogen, OH, Oxe2x80x94(C1-C6)-alkyl, Oxe2x80x94(CH2)nxe2x80x94Z, NO2, C(O)OH, C(O)xe2x80x94Oxe2x80x94(C1-C6)-alkyl, C(O)NR4R5, NR4R5 and (CH2)nxe2x80x94Z;
K, when present, is J;
K1 and R1, taken together with the nitrogen atom and the xe2x80x94C(O)xe2x80x94 group, form a 5-7 membered saturated or unsaturated heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from O, N, S and S(O2), wherein 1 to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any xe2x80x94CH2xe2x80x94 group said heterocyclic ring is optionally and independently replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2)xe2x80x94, or xe2x80x94N(R3)xe2x80x94; and wherein said heterocyclic ring is optionally fused with E;
G, when present, is xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94Yxe2x80x94, xe2x80x94C(O)xe2x80x94Yxe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(O)xe2x80x94C(O)xe2x80x94Yxe2x80x94;
Y is oxygen, or N(R6);
wherein R6 is hydrogen, E, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl; or wherein R6 and D are taken together with the atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, NH, SO, or SO2; and wherein said ring is optionally benzofused;
D is hydrogen, (C1-C7)-straight or branched alkyl, (C2-C7)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkyl or cycloalkenyl optionally substituted with (C1-C6)-straight or branched alkyl or (C2-C7)-straight or branched alkenyl or alkynyl, [(C3-C7)-alkyl]-E, [(C2-C7)-alkenyl or alkynyl]-E, or E;
wherein 1 to 2 of the CH2 groups of said alkyl, alkenyl or alkynyl chains in D is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2)xe2x80x94, or xe2x80x94N(R3);
provided that when J is hydrogen or G is selected from xe2x80x94S(O)2xe2x80x94, C(O)C(O)xe2x80x94, SO2xe2x80x94Y, C(O)xe2x80x94Y, or C(O)C(O)xe2x80x94Y, wherein Y is O; then D is not hydrogen;
m is 0 to 3; and
x is 0 or 1.
In another embodiment, the invention provides pharmaceutical compositions comprising the compounds of formula (I). These compositions may be utilized in methods treating various neurological diseases which are influenced by neuronal regeneration and axon growth or for stimulating neuronal regeneration in an ex vivo nerve cell. Examples of such diseases include peripheral nerve destruction due to physical injury or diseases such as diabetes; physical injuries to the central nervous system (e.g., brain or spinal cord); stroke; neurological disturbances due to nerve degeneration, such as Parkinson""s disease, Alzheimer""s disease, and amylotrophic lateral sclerosis.